Microneedle arrays and methods of manufacturing the same

ABSTRACT

Microneedle arrays, methods of manufacturing microneedles and methods of using microneedle arrays. The microneedles in the microneedle arrays may be in the form of tapered structures that include at least one channel formed in the outside surface of each microneedle. The microneedles may have bases that are elongated in one direction. The channels in microneedles with elongated bases may extend from one of the ends of the elongated bases towards the tips of the microneedles. The channels formed along the sides of the microneedles may optionally be terminated short of the tips of the microneedles. The microneedle arrays may also include conduit structures formed on the surface of the substrate on which the microneedle array is located. The channels in the microneedles may be in fluid communication with the conduit structures. One manner of using microneedle arrays of the present invention is in methods involving the penetration of skin to deliver medicaments or other substances and/or extract blood or tissue.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional U.S. Ser. No. 09/947,195, filed Sep. 5,2001, now allowed, the disclosure of which is herein incorporated byreference.

FIELD OF INVENTION

The present invention relates to the field of microneedle arrays.

BACKGROUND

Arrays of relatively small structures, sometimes referred to asmicroneedles or micro-pins, have been disclosed for use in connectionwith the delivery and/or removal of therapeutic agents and othersubstances through the skin and other surfaces.

The vast majority of known microneedle arrays include structures havinga capillary or passageway formed through the needle. Because the needlesare themselves small, the passageways formed in the needles must belimited in size. As a result, the passageways can be difficult tomanufacture because of their small size and the need for accuratelocation of the passageways within the needles.

Another potential problem of passageways small enough to fit within themicroneedles is that the passageways may become easily obstructed orclogged during use.

As a result, a need exists for microneedle arrays that include fluidpassageways that are easier to manufacture and that are resistant toobstruction or clogging during use.

Among the uses for microneedle arrays, penetration of skin is onecommonly-discussed application. Skin is a three-layer protective barrierbetween the body and the outside world. At approximately 200 um thick,the epidermis is the thinnest, outermost layer of the skin and itcontains many of the components that give skin it barrier-likecharacteristics. The outermost layer of the epidermis, the stratumcorneum, is a thin layer (10-50 um) of flattened, dead cells, water, andlipids that helps the body retain water and prohibits the entrance ofmicroorganisms and toxic chemicals. The stratum corneum, sometimescalled the “horny layer” is both tough and flexible, with a significantdegree of elasticity. These characteristics make the stratum corneum aneffective barrier, resistant to penetration. There is significantvariability in the thickness and elasticity of the stratum corneumassociated with age and location on the body. For example, the stratumcorneum of the feet is over ten times thicker than that found on theforearm of a typical human.

Beneath the epidermis is the dermis which houses blood vessels and nerveendings, hair shafts and sweat glands. Thousands of small capillaries(loop capillaries) feed the upper levels of the dermis, beneath theepidermis. These capillaries extend just above most of the nerve endingsthat also reside in the dermis. The deepest layer of skin, thehypodermis, insulates the body from extreme temperatures and provides amechanical cushion from outside assaults. The hypodermis contains largerblood vessels and arteries and more nerves.

Delivery of substances into the skin or removal of fluids through theskin may be facilitated by the use of microneedle arrays. One problemassociated with penetration of skin by microneedle arrays is, however,the viscoelastic properties of skin. When subjected to static orslow-moving loads, skin elongates before rupture.

As a result, many situations requiring the extraction of fluids, e.g.,blood-glucose monitoring, required the use of sharp instruments such aslancets that pierce the skin. Such devices are, however, relativelypainful to use and may pose a risk of inadvertent piercing of skin.Further, the pierced site may experience unnecessary bleeding.

SUMMARY OF THE INVENTION

The present invention provides microneedle arrays, methods ofmanufacturing molds for microneedle arrays, and methods of manufacturingmicroneedles from the molds. The microneedles in the microneedle arraysare tapered structures that include at least one channel formed in theoutside surface of each microneedle. The channels may assist in thedelivery or removal of fluids using the microneedle arrays.

In some embodiments, the microneedles include bases that are elongatedin one direction. Such a configuration may provide microneedles withimproved rigidity and structural integrity as compared to microneedlesthat do not include elongated bases. Further, the channels inmicroneedles with elongated bases may extend from one of the ends of theelongated bases towards the tips of the microneedles. That configurationmay also provide channeled microneedles with improved rigidity andstructural integrity as compared to channeled microneedles that do notinclude elongated bases.

In other embodiments, the channels formed along the sides of themicroneedles may optionally be terminated short of the tips of themicroneedles to improve the structural integrity of the tips andpotentially improve their piercing ability.

The microneedle arrays of the present invention may also include conduitstructures formed on the surface of the substrate on which themicroneedle array is located. The channels in the microneedles maypreferably be in fluid communication with the conduit structures topotentially assist with the delivery or removal of fluids through thechannels. The conduits may be formed as depressions or grooves in thesubstrate surface or they may be formed by barriers, similar to dikes,that protrude above the substrate surface.

The microneedle arrays of the invention may be used in a variety ofdifferent manners. One manner of using microneedle arrays of the presentinvention is in methods involving the penetration of skin to delivermedicaments or other substances and/or extract blood or tissue. Asdiscussed above, it may be desired that the height of the microneedlesin the microneedle arrays be sufficient to penetrate the stratumcorneum.

In addition to having a sufficient length, it may be preferred toprovide the microneedle arrays in combination with devices that arecapable of delivering the microneedle arrays to the skin in a mannerthat results in effective piercing of the stratum corneum. To do so, itmay be preferred to apply a brief impact force to the microneedle arraysuch that the microneedles on the array are rapidly driven into thestratum corneum.

It should be understood that impact delivery of microneedle arrays asdiscussed herein may not necessarily be limited to microneedle arraysthat include microneedles with channels as described in connection withFIGS. 1-4. The impact delivery devices and methods described herein maybe used with many different microneedle arrays.

In one aspect, the present invention provides a microneedle device thatincludes a plurality of microneedles projecting from a substratesurface, wherein each of the microneedles has a tapered shape with anouter surface, a base proximate the substrate surface, and a tip distalfrom the base, and further wherein the base is elongated along anelongation axis on the substrate surface such that the base has opposingends along the elongation axis. Each microneedle also includes a channelformed in the outer surface of each microneedle of the plurality ofmicroneedles, each channel extending from the base towards the tip ofthe microneedle.

In another aspect, the present invention provides a microneedle devicethat includes a plurality of microneedles projecting from a substratesurface, wherein each of the microneedles has a tapered shape with anouter surface, a base proximate the substrate surface and a tip distalfrom the base. Each of the microneedles also includes a channel formedin the outer surface of each microneedle of the plurality ofmicroneedles, each channel extending from the base of the microneedletowards the tip of the microneedle, wherein the channel terminates shortof the tip of the microneedle.

In another aspect, the present invention provides a method of deliveringa microneedle array to a skin impact site by positioning a microneedlearray proximate a delivery site, the microneedle array including aplurality of microneedles protruding from a surface; and applying animpact force to the microneedle array over a period of less than about 1second, wherein the plurality of microneedles are driven through thestratum corneum at the skin impact site.

In another aspect, the present invention provides a microneedle arraydelivery device that includes a microneedle array having a plurality ofmicroneedles protruding from a surface; a driver operably connected tothe microneedle array, wherein the driver has stored energy; whereinrelease of the stored energy results in application of an impact forceto the microneedle array over a period of less than about 1 second.

These and other features and advantages of the invention may bedescribed below in connection with various illustrative embodiments ofthe invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a perspective view of one microneedle array according to thepresent invention.

FIG. 2 is a partial cross-sectional view of two microneedles in amicroneedle array according to the present invention.

FIGS. 2A-2C are cross-sectional views of microneedles with differentlyshaped bases according to the present invention.

FIGS. 2D and 2E are cross-sectional views of alternative microneedles.

FIG. 3 is an enlarged cross-sectional view of one microneedle of FIG. 2taken along line 3-3 in FIG. 2.

FIG. 4 is a cross-sectional view of a microneedle including a channelthat terminates short of the tip of the microneedle.

FIG. 5 is a diagram of one process for manufacturing microneedle arraysaccording to the present invention.

FIG. 6 illustrates one mask useful in manufacturing a microneedle arrayaccording to the present invention.

FIG. 7 depicts use of a microneedle array in a manner according to thepresent invention.

FIG. 8 depicts contact between the microneedle array and skin asdepicted in FIG. 7.

FIG. 9 is a schematic diagram of one device for delivering microneedlearrays in accordance with methods of the present invention.

FIG. 10 depicts application of vacuum in connection with methods of thepresent invention.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention provides a microneedle array that may be usefulfor a variety of purposes. For example, the microneedles may be used todeliver or remove fluids from the point at which they are inserted. Toaccomplish that goal, the microneedles include a channel formed in theouter surface of a tapered structure. The channel extends from a base ornear a base of the microneedle towards the tip of the microneedle. Thechannel is typically formed as a void running along the side of themicroneedle. In some embodiments, the channel may extend to the tip ofthe microneedle and, in other embodiments, the channel may terminatebefore reaching the tip.

The channels formed in microneedles of the present invention can bedistinguished from bores or vias formed in known microneedles becausethey are open along substantially their entire length, e.g., from thebase of the microneedle to the terminus of the channel. In contrast,bores or vias formed in known microneedles typically are closed fluidpathways that have an opening at the tip of the needle structure.

In some embodiments, the bases of the microneedles may be elongated toimprove the rigidity and structural integrity of the microneedles. Inthe microneedles with bases that are elongated along an elongation axis,it may be preferred that the channels extend from one of the opposingends located along the elongation axis.

Additional features that may be included in the microneedle arrays ofthe present invention are conduit structures in fluid communication withthe channels formed in the microneedles. The conduit structure may beused to deliver fluids to the channels in the microneedles or they maybe used to remove fluids from the channels of the microneedles. In somesituations, the conduits and channels may both deliver and remove fluidsfrom microneedle insertion sites.

The microneedle arrays of the present invention may be used for avariety of purposes. For example, the microneedles may be used todeliver drugs or other pharmacological agents through the skin in avariation on transdermal delivery. Where the microneedles are to be usedfor transdermal drug delivery, the height of the microneedles ispreferably sufficient to pass through the stratum corneum and into theepidermis. It is also, however, preferable that the height of themicroneedles is not sufficiently large to reach the dermis, therebyavoiding contact with nerves and the corresponding potential for causingpain.

In addition to transdermal drug delivery, the microneedle arrays of thepresent invention may also find use as a mechanical attachment mechanismuseful for attaching the microneedles arrays to a variety of surfaces.For example, the microneedle arrays may be used to affix a tape or othermedical device to, e.g., the skin of a patient.

As used in connection with the present invention, the term “microneedle”(and variations thereof) refers to structures having a height above thesurface from which they protrude of about 500 micrometers or less. Insome instances, microneedles of the present invention may have a heightof about 250 micrometers or less.

Referring now to FIG. 1, a portion of one array of microneedles 20 isillustrated as arranged in rows extending in the y direction on thesurface 12 of a substrate 10. The microneedles 20 may preferably bearranged in successive rows that are, in the depicted embodiment,uniformly spaced apart in the x direction. The microneedles 20 eachinclude a channel 22 formed in the outer surface of the taperedmicroneedle.

Each of the channels 22 may be in fluid communication with an optionalconduit structure formed on the substrate surface 12 along each row ofmicroneedles 20. The conduit structures include branch arteries 32 indirect communication with the channels 22, and the branch arteries 32are in fluid communication with each other through at least one mainartery 34 of the conduit structures as depicted in FIG. 1.

The conduit structure may be formed in any suitable manner that definesfluid pathways on the substrate surface 12. The conduit structure may,for example, be formed using barriers 36 that project from the substratesurface 12. One alternative for forming conduit structure is to formdepressions or grooves into the substrate surface 12. In some instances,the conduit structure may be formed by any suitable combination ofprotruding barriers and depressions. In other instances, the conduitstructure may, in fact, include no structure, but rather be provided inthe form of a pattern of low surface energy on the substrate surface 12.The low surface energy may be provided by, e.g., coatings, surfacetreatments, etc.

Referring to FIGS. 1, 2 and 3, each of the microneedles 20 includes abase 26 on the substrate surface 12, with the microneedle terminatingabove the substrate surface in a tip 24. The base 26 may be formed inany suitable shape, although in some embodiments the base 26 may have ashape that is elongated along an elongation axis 11 on the substratesurface 12 as seen, e.g., in FIG. 2. The elongated base 26 includes twoopposing ends located opposite from each other along the elongation axis11. By providing microneedles 20 with an elongated base 26, themicroneedles 20 may exhibit improved rigidity and/or structuralintegrity during use, particularly when subjected to forces alignedalong the elongation axis 11.

In the depicted embodiment, the channel 22 is located in one of theopposing ends of the microneedle 20, where the opposing ends are locatedon opposing sides of the base 26 along the elongation axis 11. Such aconstruction may enhance the ability of the microneedle 20 to withstandshearing forces along the substrate surface 12 in the elongateddirection of the base 26.

Although the elongated microneedle base 26 illustrated in FIG. 3 is ovalin shape, it will be understood that the shape of the microneedles 20and their associated bases 26 may vary with some bases, e.g., beingelongated along one or more directions and others being symmetrical inall directions.

For example, FIG. 2A depicts an alternative microneedle 120 with aegg-shaped base 126 defining an axis of elongation 111 that is alignedbetween opposing ends of the elongated base 126. A channel 122 extendsfrom the base 126 towards the tip 124 of the microneedle 120. It shouldbe understood that the tip 124 is only an illustration of the locationof the tip projected onto the base of the microneedle 120.

FIG. 2B depicts another microneedle 220 having a tip 224 (again, aprojection of the tip) and an oval-shaped base 226 in which the channel222 is located at an intermediate location between the opposing ends ofthe base 226 (as defined by the elongation axis 211). This embodimentdepicts a microneedle in which the channel 222 is not located in one ofthe opposing ends of the microneedle 220, rather, the channel 222 islocated intermediate, i.e., between the opposing ends of the base 226.

FIG. 2C depicts another microneedle 320 according to the presentinvention in which the microneedle 320 has a tip 324 (again, aprojection of the tip) and a circular base 326 with two channels 322 aand 322 b formed in the microneedle 320. Microneedles of the presentinvention may include only one channel (as depicted in, e.g., FIGS. 1,2, 2A, and 3B) or they may include more than one channel as depicted inFIG. 2C.

The general shape of the microneedles of the present invention istapered. For example, the microneedles 20 have a larger base 26 at thesubstrate surface 12 and extend away from the substrate surface 12,tapering at a tip 24. It may be preferred, e.g., that the shape of themicroneedles be generally conical.

Although the microneedles depicted in FIG. 2 have a uniform slope orwall angle (with respect to, e.g., a z axis normal to the substratesurface 12), microneedles of the present invention may have differentwall angles. For example, FIG. 2D is a cross-sectional view of onemicroneedle 420 including a lower section 425 having steeper wall angleswith respect to the substrate surface 412, and an upper section 426having shallower wall angles proximate the tip 424 of the microneedle420.

Another variation, depicted in FIG. 2E, is that the surface of themicroneedles of the present invention need not necessarily be smooth.The sidewalls 527 of the microneedles 520 may, instead, be stepped asseen in FIG. 2E as the sidewalls move from the substrate surface 512 tothe tip 524 of the microneedle 520.

One manner in which the microneedles of the present invention may becharacterized is by height. The height of the microneedles 20 may bemeasured from the substrate surface 12 or from the top surface of thebarriers 32 forming conduits 30. It may be preferred, for example, thatthe base-to-tip height of the microneedles 20 be about 500 micrometersor less as measured from the substrate surface 12. Alternatively, it maybe preferred that the height of the microneedles 20 the about 250micrometers or less as measured from the base 26 into the tip 24.

Other potentially preferred dimensions for the microneedles 20 may bediscussed with reference to FIG. 3. It may be preferred that the largestdimension of the base 26 of microneedles 20 with an elongated oval basebe approximately 100 micrometers or less, while the shorter dimension ofthe base 26 of microneedle 20 be about 65 micrometers or less. Thesedimensions apply to microneedles with a base to tip height ofapproximately 220 micrometers.

Some exemplary dimensions for the channel 22 of microneedles 20 may alsobe described with reference to FIGS. 2 and 3. These dimensions areprovided as examples only, and are not intended to limit the scope ofthe invention unless explicitly recited in the claims. The width of thechannel 22 (as measured along the shorter dimension of the base 26) may,for example, be about 3 to about 40 micrometers.

Further, although the channels associated with microneedles of thepresent invention are depicted as having relatively smooth surfaces(see, e.g., FIGS. 2, 3, 2A-2C), the channels may preferably have asurface that is not smooth, e.g., the surfaces of the channels may beroughened, structured, etc. to enhance fluid flow.

Another manner in which microneedles having an elongated base may becharacterized is in the relationship between the dimensions of the baseand the channel. Referring to FIG. 3, it may be preferred that thechannel 22 have a channel depth measured along the elongation axis 11 atthe base of the microneedle 20 that is less than half of the dimensionof the base 26 of the microneedle 20 as measured along the elongationaxis 11.

The length of the channel 22 along microneedles 20 may also a vary. Itmay, for example, be preferred that the height of the channel 22, i.e.,its length from the base 26 to the point at which the channel 22terminates, may preferably be less than the base to tip height of themicroneedle 20. By terminating the channel 22 short of the microneedletip 24, the integrity of the tip 24 may be better maintained. Inaddition, the tip 24 of the microneedle 20 may be sharper, therebypotentially improving the ability of the microneedle 20 to pierce asurface or material against which it is pressed.

The microneedles 20 are each depicted with one channel 22 formed along aside the thereof. It should, however, be understood that microneedles ofthe present invention may be formed with more than one channel asdiscussed above. It will, also be understood that in such circumstances,the size of the channels may be reduced relative to the overall size ofthe microneedles to improve the structural characteristics of themicroneedle.

In addition to (or in place of) elongating the base of the microneedlesto improve their structural characteristics, that channel or channelsprovided in the microneedles may be terminated short of the tip of themicroneedle. Doing so may improve the structural characteristics of themicroneedles and/or may also improve the sharpness or penetrationcharacteristics of the microneedles. Referring to FIG. 4, one example ofa microneedle 620 is depicted in cross-section. The microneedle 620includes a channel 622 that terminated short of the tip 624 of themicroneedle 620. Although only one channel is depicted in themicroneedle 620 of FIG. 4, it will be understood that more than onechannel could be provided.

Returning to FIG. 2, two of the barriers 36 used to form conduitstructure as seen in FIG. 1 are depicted in cross-section. The barriers36 are provided in the form of projections from the substrate surface 12similar to the microneedles 20. The barriers 36 that form the oppositesides of the branch arteries 32 of the conduit structure are notdepicted in FIG. 2 because they are either outside the depicted view (onthe left side) or hidden behind the left-most microneedle.

As with the microneedles 20, the dimensions associated with the barriersand conduit structure formed by the barriers 36 may vary depending onthe applications for which the microneedle arrays are intended. Forexample, it may be preferred that the distance between barriers 36forming one of the branch arteries 32 in direct fluid communication withthe channels 22 in the microneedles be spaced apart from each other by adistance that is equivalent to or less than the smallest dimension ofthe channel 22 at the base 26 of the microneedle 20 as seen in, e.g.,FIG. 3. In channel 22 of FIG. 3, the smallest dimension of the channel22 is transverse to the axis 11.

By providing barriers 36 with that spacing, capillary action between thechannels 22 and the branch arteries 32 may be enhanced. Such arelationship is depicted in, e.g. FIG. 3, where the distance between thebarriers 36 along axis 11 that form the branch artery 32 is less thanthe depth of the channel 22 along the axis 11.

In another manner of characterizing the barriers 36, it may be preferredthat the height of the barriers 36 above the substrate surface 12 beselected such that the barriers 36 do not interfere with penetration ofa surface by the microneedles 20. In other words, the barrier heightshould not prevent the microneedles from reaching a desired depth.

A potential advantage of the barriers 36 forming the conduit structuresis that the barriers 36 may provide a sealing function when the array isin position against, e.g., the skin of a patient. By sealing the fluidpaths into and/or out of the channels in the microneedles 20, additionalcontrol over fluid flow within the array may be achieved.

The microneedles 20 and conduit structure may preferably be manufacturedintegrally with the substrate 10. In other words, the microneedles 20,conduit structure 30, and substrate 10 are preferably formed as a onepiece, completely integral unit. Alternatively, the microneedles and/orconduit structures may be provided separately from the substrate 10.

The microneedle arrays may be manufactured from a variety of materials.Material selection may be based on a variety of factors including theability of the material to accurately reproduce the desired pattern; thestrength and toughness of the material when formed into themicroneedles; the compatibility of the material with, for example, humanor animal skin; the compatibility of the materials with any fluids to bedelivered or removed by the channels formed in the microneedles, etc.For example, it may be preferred that the microneedle arrays of thepresent invention be manufactured of one or more metals.

Regardless of the materials used for the microneedle arrays of thepresent invention, it may be preferred that the surfaces of themicroneedle array that are likely to come into contact with fluidsduring use have certain wettability characteristics. It may be preferredthat these surfaces are hydrophilic, e.g., exhibit a static contactangle for water of less than 90 degrees (possibly less than about 40degrees), so that the fluid can be spontaneously wicked via capillarypressure. The hydrophilic nature of the surfaces may be provided byselection of materials used to manufacture the entire microneedle array,surface treatments of the entire array or only those portions likely tocome into contact with fluids, coatings on the entire array or onlythose portions likely to come into contact with fluids, etc.

Microneedles in the microneedle arrays of the present invention can besolid or porous. As used herein, the term “porous” (and variationsthereof) means having that the microneedles include pores or voidsthrough at least a portion of the structure, wherein those pores orvoids are sufficiently large and interconnected to permit at least fluidpassage.

One preferred process for forming microneedle arrays according to thepresent invention is illustrated in FIG. 5. Briefly, the method involvesproviding a substrate 40, forming a structured surface in the substrate42, the structured surface including cavities having the shape of thedesired microneedles and any other features (e.g., barriers for theconduits). A metallic microneedle array can then be electroformed on thestructured surface 44, followed by separation of the structured surfacefrom the metallic microneedle array 46.

FIG. 5 illustrates the formation of a structured surface in a substrateas the initial activity. Although the preferred method of manufacturingmicroneedle arrays according to the present invention involves laserablation of a mold substrate (using, e.g., an excimer laser) to providecavities in the shape of the desired microneedles, it should beunderstood that any suitable method of forming cavities in the desiredshape may be substituted for the method described herein. For example,the cavities may be formed by conventional photolithography, chemicaletching, ion beam etching etc. The preferred laser ablation lithographytechniques constitute only one method of forming the desiredmicroneedles arrays.

The process of forming the structured surface begins with a substratehaving sufficient thickness to allow the formation of a structuredsurface having needle cavities of the desired depth. The depth of theneedle cavities controls the height of the microneedles. As a result,the substrate used to form the structured surface must have a thicknessthat is at least equal to or greater than the desired height of themicroneedles. Preferably, the substrate used to form the structuredsurface has a thickness that is greater than the desired height of themicroneedles.

Examples of suitable materials for mold substrates used in connectionwith the present invention include, but are not limited to, polyimide,polyester, polyurethane epoxy, polystyrene, polymethylmethacrylate, andpolycarbonate. Regardless of the exact material or materials, it may bepreferred that the mold substrate be free of any inorganic fillers,e.g., silica, iron fibers, calcium carbonate, etc. One preferred moldsubstrate material is a polyimide, e.g., KAPTON H or KAPTON E fromDuPont (Wilmington, Del.), because of its ablation properties whenexposed to energy from excimer lasers.

In the case of films that are not thick enough to serve as a moldsubstrate, two or more of the films may be laminated together to providea mold substrate of suitable thickness. If a bonding agent (e.g., anadhesive) is used to laminate two films together, it may be preferredthat the bonding agent possess optical and/or ablation propertiessimilar to the films. Those material properties may include, forexample, energy absorption coefficient at a selected wavelength, auniform index of refraction; a low level of crystallinity; etc. Inaddition, it may be preferred that the bonding agent be free ofinorganic components, e.g., silica, iron fibers, calcium carbonate, etc.

The laminated substrate preferably contains no voids between films andpossesses good interlayer adhesion. As a result, it may be preferred tolaminate the films at elevated temperatures, under some pressure, and/orin a vacuum. Further, it may be desirable to treat the surface of one ormore of the films to promote adhesion and to limit void formation. Oneexample of a potentially desirable treatment is plasma etching, althoughmany other surface treatments may be used in place of, or in additionto, plasma etching.

One potentially preferred method of preparing a laminated polyimidesubstrate includes laminating two polyimide films using an epoxy (e.g.,PR-500 available from Minnesota Mining and Manufacturing Company, St.Paul, Minn.). Prior to application of the epoxy, the surfaces of thefilms are plasma etched. The epoxy may preferably be coated in a solventsolution to, e.g., enhance uniformity of the epoxy layer afterevaporation of the solvent. Following drying of the epoxy/solventsolution, the films are laminated together under heat and pressure,preferably in a sub-atmospheric pressure environment. The temperature atwhich the lamination is carried out is preferably high enough to meltthe epoxy (i.e., at or above the T_(m) of the epoxy), thereby enhancingbubble removal and uniform thickness of the epoxy layer.

After a substrate of sufficient thickness has been obtained (throughlamination or otherwise), it may be desirable to laminate the substrateto a base layer to support the substrate during laser ablation or othertechniques used to form the structured surface. The base layerpreferably maintains the substrate in a substantially planarconfiguration during processing to hold the substrate within, e.g., theobject plane of the laser ablation system during ablation. The baselayer may, for example, be glass or any other suitable material. It mayfurther be preferred that the surface of the base layer to which thesubstrate is laminated have a flatness on the order of 10 micrometers.The substrate may be laminated to the base layer using any suitabletechnique including, but not limited to, adhesives, curable resins, etc.

After the substrate is attached to the base layer, it is processed toform a structured surface including needle cavities in the shape of thedesired microneedles. As discussed above, one preferred process offorming the cavities is laser ablation using a mask. A method of usingsuch mask in connection with laser energy will be described below,although it should be understood that, unless otherwise indicated,preparation of the structured surface is not to be limited to the use oflaser energy.

One example of a mask pattern useful for forming a structured surfacefor the eventual production of an array of microneedles with channelsand conduits in fluid communication with the channels is depicted inFIG. 6. The mask pattern includes one row of needle apertures 350aligned in the x direction as seen in FIG. 6. The row of needleapertures 350 is interconnected by one set of barrier apertures 354corresponding to the barriers in the conduit structures. The barrierapertures 354 extend in both the x and y directions, i.e., along the rowof needle apertures 350 and in the y direction at the ends of thebarrier apertures. The portions of the barrier apertures 354 that extendin the y direction are used to form the barriers of the main arteries(see, e.g., FIG. 1).

In addition, each of the needle apertures 350 includes a channel feature352 corresponding to the desired location of the channel on themicroneedle corresponding to the needle aperture.

The mask itself may, e.g., be manufactured using standard semiconductorlithography mask techniques. The patterned portions of the mask areopaque to the laser energy used to pattern the substrate, e.g.,ultraviolet light in the case of excimer laser energy. The mask mayinclude a support substrate that is transparent to the laser energy. Forexample, the patterned portions may be formed of aluminum while thesupport substrate is fused silica. One alternative for the aluminum maybe a dielectric stack that is opaque for light of the desiredwavelengths.

The needle apertures 350 in the mask are preferably arranged insuccessive rows that are uniformly spaced apart (along the x axis). Itis further preferred that the spacing between the needle apertures alongthe rows are also uniform (along the y axis). With uniform spacingbetween the needle apertures and associated conduit apertures, laserablation processes similar in many respects to those described inInternational Publication No. WO 96/33839 (Fleming et al.) and its U.S.priority applications, can be used to form cavities in the substrate.

One of the ways in which the preferred laser ablation process differsfrom that disclosed in WO 96/33839 is that a telecentric imaging systemis used to deliver laser energy to the mask. The telecentric imagingsystem provides principal rays that are parallel to the optical axis. Asa result, the image does not change size when out of focus. In addition,projected features at the center of the mask are the same size as thosefound at the edges of the mask.

By providing both the needle apertures and the barrier apertures in thesame mask, the present invention provides a number of advantages. Amongthose advantages is the ability to provide microneedles and theassociated conduit structures in registration with each other becausethe features can be imaged at the same time. This can be particularlyimportant in producing devices such as microneedle arrays in which thefeatures are spaced apart in distances measured in micrometers.

Control over the depth of the different cavities formed in the substrate(corresponding to the different heights of the microneedles and barrierson the microneedle arrays) can be obtained by, e.g., selectivelycovering or masking the different features on the mask while ablatingthe underlying substrate through the apertures that are not covered ormasked. That process can be used, e.g., to obtain barrier cavities thatare shallower than the microneedle cavities.

Use of the mask pattern depicted in FIG. 6, for example, may proceedwith a first exposure of the substrate located beneath portion A of themask pattern, i.e., the row of needle apertures 350 interconnected bythe barrier apertures 354. As a result, the substrate is exposed duringthe first exposure in a pattern corresponding to portion A of the maskpattern.

Movement of the mask pattern and the substrate being exposed relative toeach other in the y direction can then be used to align the maskapertures 350 in the uppermost row of portion B with the parts of thesubstrate exposed by the needle apertures 350 in portion A during thefirst exposure. A second exposure then results in another exposurethrough the needle apertures to ablate more of the substrate, therebyincreasing the depth of the needle cavities in the substrate withoutalso increasing the depth of the barrier cavities. Step-wise movementand exposure can then be repeated until the needle cavities and thebarrier cavities are formed to the desired depth in the substrate.

Control over the wall angles of the needle cavities may be achieved byany suitable technique or combination of techniques. Examples ofsuitable techniques may be described in, e.g., T. Hodapp et el.,“Modeling Topology Formation During Laser Ablation,” J. Appl. Physics,Vol. 84, No. 1, pp. 577-583 (Jul. 1, 1998).

When processing a polyimide mold substrate through laser ablation, itmay be preferred that the mold substrate be located in an oxygenatmosphere to improve subsequent plating of the cavities thus formed.

After completion of the structured surface, the substrate provides anegative of the desired microneedle array structure, with needlecavities corresponding to the shape of the microneedles and conduitcavities corresponding to the desired shape of the conduit structures.As for the needle cavities, they are preferably generally tapered inshape, with a channel structure extending into the tapered shape of theneedle cavity.

The resulting mold substrate is then preferably electroplated to form ametallic positive of the microneedle array. Before electroplating,however, the substrate may preferably be cleaned to remove any debristhat is, e.g., associated with the laser ablation processing used toform the negative image in the substrate. One suitable cleaning processmay include locating the substrate in an ultrasonic bath of detergentand water, followed by drying.

After cleaning the mold substrate, a seed layer of one or moreconductive metals is preferably first deposited to provide a conductivesurface, followed by heavier electroplating in, e.g., a nickel bath. Theseed layer may be deposited by sputtering, chemical vapor deposition, asilver bath, or any other suitable method. To enhance proper filling ofthe cavities and fidelity of the resulting microneedles to the shape ofthe cavities, it may be preferred that the seeding be continued until athicker seed layer is deposited. For example, it may be preferred thatthe seed layer be deposited with a thickness of about 0.5 micrometers ormore, possibly even about 1 micrometer.

Following formation of the seed layer, the seeded mold substrate canthen be electroformed with a thicker layer of, e.g., nickel, to form ametallic microneedle array. After filling the cavities in the moldsubstrate, the plating process is preferably continued until a backplateis formed on the mold substrate with a thickness sufficient to supportthe microneedle array. For example, a backplate with a thickness ofabout 0.5 millimeters to about 3 millimeters or more may be formed. Ifdesired, the surface of the backplate opposite the microneedlestructures may be polished. That polishing may preferably be carried outwhile the substrate is still attached to a base layer as describedabove.

After the metallic microneedle array is formed, the mold substrate canbe removed from the microneedle array by any suitable technique orcombination of techniques. Some suitable techniques include, but are notlimited to, chemical etching, shock freezing, laser ablation, etc. Forexample, a polyimide substrate may be removed from a microneedle arrayusing an etchant, e.g., potassium hydroxide (KOH).

Because the needle cavities in the structured surface may have arelatively high aspect ratio, it may be desirable to use anelectroplating process capable of accurately filling the high aspectratio cavities. For example, it may be desirable to carry out theelectroplating process in the presence of ultrasonic energy for at leasta portion of the electroplating. Examples of some suitable systems forand processes of electroplating in the presence of ultrasonic energy maybe described in e.g., U.S. Pat. No. 6,746,590 (H. Zhang et al.).

The microneedle arrays of the invention may be used in a variety ofdifferent manners. One manner of using microneedle arrays of the presentinvention is in methods involving the penetration of skin to delivermedicaments or other substances and/or extract blood or tissue. Asdiscussed above, it may be desired that the height of the microneedlesin the microneedle arrays be sufficient to penetrate the stratumcorneum.

Microneedle Array Delivery

In addition to having a sufficient length, it may be preferred toprovide the microneedle arrays in combination with devices that arecapable of delivering the microneedle arrays to a skin impact site in amanner that results in effective piercing of the stratum corneum by themicroneedles on the array. Delivery of a microneedle array in accordancewith the methods of the present invention will involve application of animpact force to the microneedle array over a short period of time(typically less than about 1 second) such that the microneedles of thearray are driven through the stratum corneum at the skin impact site.Application of the impact force may rapidly accelerate the microneedlearrays of the present invention such that impact delivery of themicroneedle array with the skin is achieved.

It should be understood that impact delivery of microneedle arrays asdiscussed herein may not necessarily be limited to microneedle arraysthat include microneedles with channels as described above in connectionwith FIGS. 1-6. The impact delivery devices and methods described hereinmay be used with many different microneedle arrays.

Referring to FIG. 7, one method of forcing a microneedle array 60including microneedles 62 is depicted, with the microneedle array 60being forced against the skin 70 (with stratum corneum 72) by an impactforce 64. FIG. 8 depicts the microneedle array 60 in contact with theskin 70, such that the microneedles 62 penetrate the stratum corneum 72.

The impact force magnitude and duration period are selected to provideeffective penetration of the stratum corneum by the microneedles. It maybe preferred that the period of time over which the impact force isapplied be less than about 500 milliseconds, in some instances, theperiod may preferably be about 300 milliseconds or less.

The impact force may be applied in a variety of manners. For example,the microneedle array 60 may be positioned a distance from the skinimpact site, such that application of the impact force 64 results inacceleration of the microneedle array 60 towards the skin impact siteuntil the microneedle array contacts the skin impact site. In anotherexample, the microneedle array may be positioned in contact with theskin impact site before the impact force is applied to the microneedlearray, such that application of the force does not result inacceleration as would be achieved if the microneedle array is positionedaway from the skin.

After application of the impact force and subsequent driving of themicroneedles through the stratum corneum, it may be desired to removethe microneedle array from contact with the skin impact site withinabout 1 second or less. In other instances, it may be desirable toretain the microneedle array in contact with the skin impact site for alonger period of time, e.g., about 2 seconds or more.

The maximum magnitude of the impact force may preferably be limited to,e.g., control the pain associated with impact delivery of microneedlesarrays in connection with the present invention. For example, it may bepreferred to provide impact delivery of the microneedle arrays of thepresent invention with a maximum impact force about 40 N/cm² or less,more preferably about 20 N/cm².

At the other end of the force spectrum, the minimum impact force mayvary depending on a variety of factors such as the size of themicroneedle array, the size and/or shape of the microneedles, etc.

A wide variety of devices may be used to provide the desired impactdelivery of microneedle arrays with the skin of a subject. One suchdevice 68 is illustrated schematically in FIG. 9 as including amicroneedle array 60 and a driver 66. The device 68 may be a single-usedisposable design, it may be designed for using a single microneedlearray 60, or it may be designed to use multiple different microneedlesarrays 60.

The driver 66 may be provided by any mechanism capable of applying thedesired impact force needed to drive the microneedles into the stratumcorneum as discussed above. The driver 66 may be in the form of anydevice capable of releasing stored energy in the form of the impactforce over the durations discussed above, i.e., over a period of lessthan about 1 second. For example, the driver 66 may include a mechanicalspring (e.g., a coil spring, leaf spring, etc.), compressed resilientmember (e.g., rubber, etc.), compressed fluids (e.g., air, liquids,etc.), piezoelectric structure, electromagnetic structure, hammerdevice, etc.

One example of a potentially suitable device 68 may include a lancetdriver incorporating a mechanical spring which may be modified, ifneeded, to provide the desired force to the microneedle array.Typically, a lancet driver may also require some modifications to ensurethat the microneedle array is forced against the skin in a manner suchthat substantially all of the microneedles contact the skin.

Following impact delivery of a microneedle array according to thepresent invention, it may be desirable to provide vacuum over thesurface of the skin impacted by the microneedle array. Application ofvacuum to the impact site can be used to extract blood or fluid from theskin penetrated by the microneedles.

Referring to FIG. 10, a vacuum cup 90 is depicted over the skin impactsite as depicted in, e.g., FIG. 8. The vacuum cup 90 may preferablyinclude a port 94 that allows for evacuation of the volume 92 defined bythe vacuum cup 90. As used in connection with the present invention,“vacuum” is defined as a pressure below the ambient atmospheric pressuresurrounding the vacuum cup. The vacuum may be provided by any suitablesource, e.g., a pump, syringe, etc.

The microneedles driven into the stratum corneum at the skin deliverysite may provide fluid pathways through the stratum corneum. A vacuumapplied over the skin delivery site after the microneedles have beendriven into the stratum corneum may enhance the passage of fluidsthrough the stratum corneum within the skin delivery site.

The ability of the vacuum drawn within volume 92 to draw fluids throughthe skin in the skin impact site may be used for a variety of purposes.For example, an indicator 80 capable of detecting the presence orabsence of substances or materials in fluids drawn out from the skinimpact site may be located on the skin impact site. The indicator 80 maybe placed in contact with the skin delivery site before drawing thevacuum over that site or after drawing the vacuum over the skin impactsite.

For example, a blood glucose monitoring strip 80 may be placed over theskin impact site with the fluid drawn through the impact site activatingthe strip to provide a glucose reading. In such a method, sufficientfluid may be drawn under, e.g., conditions of 0.5 atm of vacuum for lessthan 1 minute.

In addition to indicators for determining blood-glucose levels, thedevice and methods of the present invention may be used to extract fluidfor other indicators such as those capable of determining the presence,absence or amounts of a variety of materials in fluids (e.g., blood)such as dissolved oxygen, carbon dioxide, lactic acid, illicit drugs,etc.

Additionally, the demonstration of effective penetration of the stratumcorneum may provide a useful pathway for localized, painlessadministration of pharmaceuticals. Topically applied pharmaceuticals maybe more effectively delivered through the skin after penetration of thestratum corneum by the microneedle arrays of the present invention. Inother variations, the microneedle array penetration may be coupled withan electrical or ultrasonic device to deliver larger drugs through theskin more rapidly that is possible through uncompromised tissue.

Where used for the delivery of medicaments or other substances (or theremoval of fluids), it may be desirable to include one or morereservoirs in fluid communication with the conduit structures formed inthe microneedle arrays. Examples of such reservoirs may be described in,e.g., U.S. Pat. No. 3,964,482 (Gerstel et al.). The reservoirs may be influid communication with the conduit structures on the front side of themicroneedle arrays (i.e., the side from which the microneedles project)or they may be in fluid communication with the conduit structure fromthe back side (i.e., the side opposite the front side) through vias orother fluid pathways.

All patents, patent applications, and publications cited herein are eachincorporated herein by reference in their entirety, as if individuallyincorporated by reference. Various modifications and alterations of thisinvention will become apparent to those skilled in the art withoutdeparting from the scope of this invention, and it should be understoodthat this invention is not to be unduly limited to the illustrativeembodiments set forth herein.

1. A method of delivering a microneedle array to a skin impact site, themethod comprising: positioning a microneedle array proximate a deliverysite, the microneedle array comprising a plurality of microneedlesprotruding from a surface; applying an impact force to the microneedlearray over a period of less than about 1 second, wherein the pluralityof microneedles are driven through the stratum corneum at the skinimpact site.
 2. A method according to claim 1, wherein the period isless than about 500 milliseconds.
 3. A method according to claim 1,wherein the period is less than about 300 milliseconds.
 4. A methodaccording to claim 1, wherein applying the impact force to themicroneedles array comprises accelerating the microneedle array towardsthe skin impact site.
 5. A method according to claim 1, wherein themicroneedle array is in contact with the skin impact site beforeapplying the impact force to the microneedle array.
 6. A methodaccording to claim 1, further comprising removing the microneedle arrayfrom contact with the skin impact site within about 1 second after theplurality of microneedles are driven through the stratum corneum at theskin impact site.
 7. A method according to claim 1, further comprisingretaining the microneedle array in contact with the skin impact site forabout 2 seconds or more after the plurality of microneedles are driventhrough the stratum corneum at the skin impact site.
 8. A methodaccording to claim 1, wherein the impact force has a maximum of about 40N/cm² or less.
 9. A method according to claim 1, wherein the impactforce has a maximum of about 20 N/cm² or less.
 10. A method according toclaim 1, further comprising drawing a vacuum at the skin impact siteafter the plurality of microneedles are driven through the stratumcorneum at the skin impact site.
 11. A method according to claim 1,further comprising locating an indicator in contact with the skin impactsite after the plurality of microneedles are driven through the stratumcorneum at the skin impact site.
 12. A method according to claim 1,wherein the method further comprises: locating an indicator in contactwith the skin impact site after the plurality of microneedles are driventhrough the stratum corneum at the skin impact site; and drawing avacuum at the skin impact site after the plurality of microneedles aredriven through the stratum corneum at the skin impact site.
 13. Amicroneedle array delivery device comprising: a microneedle arraycomprising a plurality of microneedles protruding from a surface; adriver operably connected to the microneedle array, wherein the drivercomprises stored energy; wherein release of the stored energy results inapplication of an impact force to the microneedle array over a period ofless than about 1 second.
 14. A device according to claim 13, whereinthe driver comprises at least one mechanical spring.
 15. A methodaccording to claim 13, wherein the driver comprises at least oneresilient member.
 16. A method according to claim 13, wherein the drivercomprises a compressed fluid.